There has been a considerable research interest in the area of particulate delivery systems as carriers for small and large molecules. The concept of using particles to deliver therapeutic agents has gained tremendous interest over years. Particulate delivery systems can change the fate of a drug without modifying the chemical structure, and increase efficacy and decrease toxicity of a drug. Some particulate drug delivery systems having better capability to overcome physiological barriers, precisely control the release rates, or target drugs to a specific body site, have a marked impact on the health care system.
Particulate systems especially nano- and micro scale based systems offer versatility by virtue of their small size and efficient carrier characteristics, enabling the tailoring of delivery systems with consideration of the biological target, desired pharmacokinetic profile, and route of administration. Both nano scale (1-100 nm) and micro scale (0.1-1000 μm) systems have been extremely important in developing various clinically useful particulate delivery systems. Nanotechnology has been strategically used for developing such particulate delivery systems.
Nanocarriers and microcarriers such as nanoparticles, nanospheres, nanoemulsions, nanocapsules, liposomes, micelles, microparticles, microspheres, and the like demonstrate a broad variety of useful properties, such as controlled or modified drug release; uptake through biological membranes, longevity in the blood allowing for their accumulation in pathological areas with compromised vasculature; specific targeting to certain disease sites due to various targeting ligands attached to the surface of the carriers; enhanced intracellular penetration with the help of surface-attached cell-penetrating molecules; contrast properties due to the carrier loading with various contrast materials allowing for direct carrier visualization in vivo; stimuli-sensitivity allowing for drug release from the carriers under certain physiological conditions, and others.
Such nano- and micro scale based particulate delivery systems comprising multitude of particulate units also provide many advantages over single-unit systems or systems having larger particle size, like reduced risk of local irritation and toxicity, predictable bioavailability, reduced likelihood of dose dumping, minimized fluctuations in the plasma concentration of the biological agent, high dose-strength administration, reduced risk of systemic toxicity and site specific or targeted therapeutic effect, controllable particle size, flexibility of delivering by various routes of administration, more reproducible pharmacokinetic behavior, lower intra- and inter-subject variability than conventional single unit formulations.
Many attempts have been made towards the preparation of particulate delivery systems employing different nanotechnology processes and different particulate carrier materials. U.S. Pat. No. 5,766,635 discloses preparation of nanoparticles by dissolving a poly (ethylene oxide) and/or poly (propylene oxide) polylactic copolymer in an organic solvent followed by mixing the solution containing the polymer with an aqueous solution and by precipitation or by microfluidization and solvent evaporation. U.S. Pat. No. 8,293,276 discloses methods of making nanoparticles having about 0.2 to about 35 weight percent of a therapeutic agent; and about 10 to about 99 weight percent of a polymer such as a diblock poly (lactic) acid-poly (ethylene) glycol. Schubert et al. describe in Journal of Polymer Science, Part A, Polymer Chemistry, Vol. 48, 3924-3931, 2010, the preparation of nanoparticles from solutions of poly (methyl methacrylate) and its copolymers by nanoprecipitation method. US Patent Application 20100297237 discloses a pharmaceutical composition comprising nanoparticles comprising: a poorly water soluble drug; a poorly aqueous soluble non-ionizable polymer selected from the group consisting of ethylcellulose, cellulose acetate, cellulose propionate, cellulose butyrate, cellulose acetate butyrate, and mixtures thereof; and an amine-functionalized methacrylate copolymer, poly [ethylacrylate-co-methyl methacrylate-co-trimethylamonioethyl methacrylate chloride].
Though various attempts have been made to develop particulate delivery systems using synthetic polymers, these polymers may be toxic, non-biodegradable, allergic, incompatible with some drugs, or not economical. Natural excipients are therefore employed in particulate delivery systems as they are inert, safe, non-toxic, biocompatible, biodegradable, economical, eco-friendly and abundantly available in nature compared to the synthetic polymers. Natural polysaccharides have been widely investigated for their benefits in particulate delivery systems.
Polysaccharides consist of long carbohydrate molecules containing repeated monosaccharide units which are joined together by means of glycosidic bonds. They represent the most abundant biomolecules in nature. Polysaccharides are highly biocompatible and biodegradable. They can be classified by their origin: vegetal origin (e.g. pectin), algal origin (e.g. alginate), microbial origin (e.g. dextran, xanthan gum), and animal origin (chitosan, heparin). Polysaccharides may also be classified by their charge: cationic (chitosan), anionic (hyaluronic acid, heparin) and nonionic (dextran). Polysaccharides can be homopolysaccharides or heteropolysaccharides depending on their monosaccharide components. A variety of particulate delivery systems have been attempted using different polysaccharides.
U.S. Pat. No. 6,677,386 discloses a process for producing starch nanoparticles in which the starch is plasticized using shear forces and a crosslinking agent is added during the processing. After the processing, starch was dissolved or dispersed in an aqueous medium to a concentration between 4 and 40 wt. % which results in starch nanoparticles that are characterized by an average particle size of less than 400 nm. Preparation of nanoparticles using other natural polysaccharides has also been discussed. U.S. Pat. No. 8,389,012 discusses nanoparticulate controlled-release composition containing gellan gum and polyethylene glycol and their methods of preparation. PCT Publication WO2007/042572 provides nanoparticulate systems comprising chitosan, and optionally a polyoxyethynylenated derivative which are ionically crosslinked for the controlled release of heparin. Senthil et al describe in World Journal of Pharmacy and Pharmaceutical Sciences, Volume 3, Issue 9, 978-1015, 2014, the development and evaluation of enteric coated guar gum nanoparticles of antiprotozoal fixed drugs combination of Tinidazole and Norfloxacin for treatment of amoebiasis. Guar gum nanoparticles were prepared by double step w/o/w emulsion method, cross linking with glutaraldehyde and enteric coated by solvent evaporation method to protect the drugs in gastric fluids and achieve a targeted drug delivery.
The majority of natural polysaccharides present several hydrophilic groups such as carboxyl, hydroxyl and amino groups, which endow their solubility in water and the formation of non-covalent bonds with biological tissues and mucosal membranes. This way, the hydrophilic properties of most of the polysaccharide nanoparticles provide bioadhesion and mucoadhesion characteristics to these biomaterials, as well as the possibility of chemical modification of the macromolecules to bind drugs or targeting agents. The hydrophilic nanoparticles also possess the enormous advantage of extended circulation in blood, which increases the probability of passive targeting of the nanoparticles into the tumor tissues. Though a number of benefits are associated with the use of natural polysaccharides in particulate delivery systems, certain drawbacks such as batch to batch variation, low drug release predictability as well as other disadvantages otherwise associated with particulate delivery systems such as erratic release profile, low drug loading capacity, particle-particle aggregation may however exist. A need therefore exists to identify and evaluate newer natural biomaterials as carrier materials for particulate delivery systems that can overcome one or more of the drawbacks of natural excipient based particulate systems.
The present inventors after rigorous experimentation have identified unexpected benefits associated with the use of fenugreek gum as a carrier material in particulate delivery systems. The present inventors provide particulate delivery systems comprising plurality of particles comprising fenugreek gum and at least one pharmaceutically acceptable excipient. The systems of the present invention overcome one or more of the drawbacks associated with particulate delivery systems and/or use of natural polysaccharides therein as mentioned hereinabove. Fenugreek gum has not been reported previously by researchers to be useful as a carrier material for preparation of plurality of particles for particulate delivery systems. Fenugreek gum employed in the particulate delivery systems of the present invention serves as a non-toxic, ecofriendly, economical biodegradable alternative to existing natural polysaccharides and is amenable to nanotechnological processes for the development of particulate delivery systems of a variety of therapeutic, immunologic, or diagnostic agents, for controlled delivery, targeting to specific biological tissues, improved stability and the like.